Chemo-enzymatic process for the preparation of opticaly enriched β-benzyl-γ-butyrolactones

ABSTRACT

The present invention relates to a novel synthetic process for the enriched preparation of substituted R(+)β-benzyl-γ-butyrolactone (1) as shown in the drawing wherein R 1  and R 2  independently or in combination represent the following groups: i.e. R 1 ═R 2 ═H, —OC n H 2n+1  (where n=1 to 8); R 1 , and R 2  together represents —O(CH 2 ) m O— (where m=2 to 4)

FIELD OF THE INVENTION

The present invention relates to a novel process for the enrichedpreparation of substituted R(+)β-benzyl-γ-butyrolactones of the formula(1).

BACKGROUND AND PRIOR ART REFERENCES

Substituted β-benzyl-γ-butyrolactones are known for their biologicalproperties such as anticancer activities and they are also the keyintermediates in the synthesis of butyrolactone lignans as well as othernatural products. Due to various pharmacological and medicinalproperties associated with butyrolactones and related lignans, thechemical synthesis of the intermediate butyrolactones has been the majortarget of several synthetic schemes. One of the more common syntheticstrategies utilizes Stobbes condensation of an aromatic aldehyde withalkyl succinates followed by selective reduction (Banerji, J.,Biswanath, D. Heterocycles, 1985, 23(3), 661–5 (b) Shao, L., Miyato, S.,Muramatsui, H., Kawano, H., Ishi, Y., Soburi, M., Uchida, Y. J. Chem.Soc. Perkin Trans. (I), 1990, 5, 1441–5 (c) Marimoto, T., Chiba, M.,Achiwa, K. Tetrahedron, 1993, 49(9), 1793–806). Besides several novelsynthetic methodologies have also been reported for the asymmetrisationof the butyrolactones and the lignans[(a) Vanderlei, J. M. de. L.,Coelho, F. and Almeida, W. P. Synth. Comm. 1998, 28(16), 3047–55. (b)Canton, J. L. Can. J. Chem. 1997, 75(8), 1076–83. (c) Filho, H. C. A.,Filho, U. F. L., Pinheiro, S., Vasconcells, M. L. L. A., Costa, P. R. R.Tetrahedron Asymm. 1994, 5(7), 1219–20 9 (d) Costo Paulo, R. R. V.Ferreiro J. Braz. Chem Soc., 1996, 7(1), 67–73. Chem. Abstr.I24:26068Iy].

In recent years asymmetric syntheses of optically active butyrolactonesand corresponding lignans have also been achieved using thechemo-enzymatic methods [(a) Vanderlei, I. M. de. L., Coelho, F. andAlmeida, W. P. Synth. Comm. 1998, 28(16), 3047–55. (b) Caniton, J. L.Can. J. Chem. 1997, 75(8), 1076–83. (c) Filho, H. C. A., Filho, U. F.L., Pinheiro, S., Vasconcells, M. L. L. A., Costa, P. R. R. TetrahedronAsymm. 1994, 5(7), 1219–20 9 (d) Costo Paulo, R. R. V. Ferreiro J. Braz.Chem Soc., 1996, 7(1), 67–73. Chem. Abstr. 124:260681y].

Most of the known processes or synthesis of substitutedβ-benzyl-γ-butyrolactones are either inconvenient to carry out on higherscale because of the complexity of the reactions or due to theunavailability of the starting materials. These methods also suffer fromlow over all yields. They also involve complex experimental conditions,which are lacking reproducibility.

OBJECTS OF THE INVENTION

Main object of the invention is to provide a synthetic process for theenriched preparation of R(+)β-benzyl-γ-butyrolactone (1) as shown in theaccompanying drawing.

Another object of the invention is to provide a economical andenvironmental friendly process for the preparation ofR(+)β-benzyl-γ-butyrolactone.

Still another object of the invention is to provide a chemo-enzymaticreduction for generation of chirality.

Yet another object of the invention is to provide chemo-enzymaticreduction and cyclization process for the intermediates to achieveenriched optically active form of the final compound.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a novel synthetic processfor the enriched preparation of substituted R(+)β-benzyl-γ-butyrolactone(1) as shown in the drawing wherein R₁ and R₂ independently or incombination represent the following groups: i.e. R₁═R₂═H,—OC_(n)H_(2n+1) (where n=1 to 8); R₁ and R₂ together represents—O(CH₂)_(m)O— (where m=2 to 4)

BRIEF DESCRIPTION OF THE DRAWINGS

The figure (FIG. 1) illustrates the general formula of the process ofthe present invention, shown as formula 1, and additionally illustrates,according to the present invention, the substituted alkoxybenzene asformula 2, the 4-keto-4-phenyl-butyric acid as formula 3, the4-keto-4-phenyl butyrate as formula 4, the secondary alcohol4-hydroxy-4-phenyl butyrate as formula 5, the4-phenyl-3-formyl-3ene-butrylate as formula 6, and the dihydro primaryalcohol as formula 7.

DETAILED DESCRIPTION OF THE INVENTION

The present invention therefore discloses a novel, facile and enrichedprocess for the synthesis of substituted R(+)β-benzyl-γ-butyrolactoneswith moderate to high overall yield.

The present invention is directed to chemo-enzymatic process ofpreparation of optically enriched substitutedR(+)β-benzyl-γ-butyrolactones (1). The process particularly relates to anovel chemo-enzymatic process for the preparation of optically enriched4-(alkoxy phenyl)-methyl-γ-butyrolactones

The present invention relates to a novel process for the enrichedpreparation of substituted R(+)β-benzyl-γ-butyrolactones of the general1 as shown below,

wherein,

R₁ and R₂ independently or in combination represent the following groups

R₁═R₂═H, —OC_(n)H₂ _(n+1) where n=1 to 8

R₁ and R₂ together represents —O(CH₂)_(m)O— where m=2 to 4 and saidprocess comprises the steps of:

-   a) reacting the requisite substituted alkoxybenzene (2) where R₁ and    R₂ has independently the same definition as mentioned earlier, with    succinic anhydride in presence of a Lewis acid in an inert solvent,-   b) esterification of the resulting product 4-keto-4-phenyl-butyric    acid (3) of step (a) to yield 4-keto-4-phenyl butyrate (4),-   c) reducing the keto group of compound (4) of step (c) to yield the    corresponding secondary alcohol 4-hydroxy-4-phenyl butyrate (5),-   d) reacting the compound (5) of step (c) with a reagent prepared    from equimolar mixture of phosphoryl chloride and dimethyl formamide    to produce 4-phenyl 3-formyl-3ene-butryrate (6),-   e) bio-reduction of the unsaturated formyl ester (6) of step (d)    with a micro-organism or an enzyme to produce optically enriched    R(+) primary alcohol (7); and-   f) cyclisation of the primary dihydro alcohol (7) of step (e) with    dilute mineral acid to produce substituted    R(+)β-benzyl-γ-butyrolactone (1) where R₁ and R₂ represents any one    of the groups as mentioned above.

In an embodiment of the present invention, alternatively opticallyenriched substituted R(+)β-benzyl-γ-butyrolactone (1) is directlyobtained by bio-reduction of the unsaturated formyl ester (6) obtainedfrom step (e) with a micro-organism or enzyme selected from Baker'syeast, Candida sp., Pichia sp.

In another embodiment of the present invention wherein, R₁ and R₂substituents of alkoxy benzene (2) have the same meaning as mentionedearlier, which is reacted with succinic anhydride in presence of a Lewisacid selected from a group consisting of anhydrous aluminum trichloride,aluminum tribromide, zinc chloride and boron trifluoride ethereatepreferably aluminum chloride.

Yet another embodiment of the invention wherein in step (a), thereaction of succinic anhydride is carried out using an inert organicsolvent selected from the group consisting of nitromethane, carbondisulfide and/or benzene.

Yet another embodiment of the invention wherein in step (b), theesterification of (3) is carried out with an alcohol in presence of anacid selected from a group consisting of sulfuric acid, hydrochloricacid and phosphoric acid and alcohol selected from methanol, ethanoland/or propanol.

Yet another embodiment of the invention wherein in step (c), thereduction of the keto ester is performed in presence of hydrogen gasusing metal catalyst supported on activated charcoal selected from agroup consisting of palladium, platinum and nickel. Yet anotherembodiment of the invention wherein in step (c), the reduction of theketo function may also be carried out using metal hydride reagentsselected from a group consisting of sodium borohydride, and sodiumcyanoborohydride preferably in an aqueous medium or lithium aluminumhydride in an inert organic solvent selected from diethyl ethrr,tetrahydrofuran or admixtures thereof.

Yet another embodiment of the invention wherein in step (d), formylationof the hydroxy ester (4) is carried out at a temperature ranging between−5° C. to 50° C. using formylating reagent prepared from equimolarmixture of phosphoryl trichloride and dimethyl formamide.

Yet another embodiment of the invention wherein in step (e),bioreduction of the prochiral αβ-unsaturated formyl ester is effected byan microorganism or yeast enzyme selected from group consisting ofBaker's yeast, Candida sp., Pichia sp.

Yet another embodiment of the invention wherein in step (f), theoptically enriched dihydrohydroxymethyl ester (7) is cyclised to produce(1) with a dilute mineral acid selected from a group consisting ofsulfuric acid, hydrochloric acid and phosphoric acid. The Lewis acid maybe selected preferably from anhydrous aluminum chloride, aluminiumtribromide, boron trifluoride, zinc chloride but more preferablyaluminium trichloride in an inert organic solvent selected fromnitrobenzene, carbon disulphide, benzene but more preferablynitrobenzene.

The esterification of the acid (3) is carried out with an anhydrousalcohol preferably methanol, ethanol, propanol more preferably methanolin presence of an acid such as concentrated hydrochloric acid, sulphuricacid, phosphoric acid but more preferably sulphuric acid. Alternativelythe esterification may also be effected by freshly prepared diazomethaneto produce methyl ester (4) in quantitative-yield.

The conversion of substituted 4-keto-4-phenyl butyrate (4) 3 to hydroxyester (5) is preferably carried out by catalytic reduction using 5% to10% palladium or platinum on activated charcoal in an alcoholic solventin presence of hydrogen gas. Alternatively, reduction may also beeffected using metal hydride reagents such as sodium borohydride,preferably in an inert or an alcoholic or aqueous medium. It is furtherpreferred that metal hydride such as lithium aluminum hydride reagent isused in an inert solvent such as diethyl ether, tetrahydrofuran oradmixture thereof.

The formylating reagent prepared from one mole each of phophorylchloride and dimethyl formamide is reacted with the compound (5) at −10°C. to 50° C. more preferably at −5° C. to +50° C. to furnish prochiralαβ-unsaturated aldehyde (6). The bioreduction of the compound (6) whereR₁ and R₂ has same definition as described above, is performed using abio-catalyst or an enzyme which stereoselectively reduces the doublebond as well as capable of simultaneously converting aldehyde functionto a primary alcoholic function. The more preferred bio-catalyst toproduce optically enriched in R(+) enantiomer (7) is the use of Baker'syeast in which the bioreduction is carried out at 10° to 50° C.preferably at 20° C. to 35° C. The pH of the aqueous medium containingD-glucose for bio-reduction is maintained between 6 to 8 more preferablybetween 6.5 to 7.3. The cyclisation of the intermediate hydroxymethylester (7) is prepared as above where the substitiuents R₁ and R₂ havethe same meaning as mentioned earlier, preferably effected by a using amineral acid in an aqueous medium. The preferred acid for cyclisation ofcompound (7) is hydrochloric acid (20%). Alternatively, thebio-reduction as well as cyclisation to furnish the optically enrichedfinal compound is completed in a single step.

In the preferred embodiment use of the term optically enrichedR-(+)-β-benzyl-γ-butyrolactone (1) 1 is intended to signify theformation of both (R) and (S) stereoisomers of β-benzyl-γ-butyrolactone(1) wherein one of the stereoisomer i.e. R(+) optical isomer is in largeexcess, therefore the mixture has overall +ve sign of optical rotationwith (R) configuration.

The invention is described in examples given below which are given byway of illustration only and therefore these examples should not beconstrued as to restrict the scope of the invention.

EXAMPLE-1

Step-1

Preparation of 4-(3,4-dimethoxyphenyl)-4-oxo-butyric acid (3)R₁═R₂═OCH₃)

In a three necked flask fitted with a guard tube, a mixture of veratrole(3,4-dimethoxy benzene, 2) (7.0 g, <SOmmol) and anhydrous aluminumchloride (16 g) in nitrobenzene (50 ml) stirred at 0–5° C. and to themixture is added drop wise a solution of succinic anhydride (6 g., 60mmol) in nitrobenzene (60 ml). After the addition is over, the stirringmixture is allowed to attain room temperature and heated up to 60° C.for further three hours till the evolution of hydrochloric acidsubsides. The reaction mixture is cooled, poured into ice cold water(200 ml) and the resulting precipitate is filtered, washed with water.The dried crude acid 3 (10.6 g. 89%) is crystallized from methanol:ethyl acetate (1:9) as colorless powder mp 162–63° C., it is analyzedfor C₁₂H₁₄O₅ (found C, 61.44%, H, 5.88% requires C60.49%; H 5.92%).

¹H NMR (CD₃OD): 2.67 (2H, t, J=6.6 Hz, H-2), 3.27(2H, t, J=6.6 Hz, H-3),3.86 & 3.89(6H, 2xs, 2xOCH3), 7.02(1H, d, J=8.5 Hz, Ar—H), 7.65(1H, d,J=2.0 Hz, Ar—H), 7.68(1H, dd, J=8.5 & 2.0 Hz, Ar—H).

IR (KBr): 3382, 2940, 1730, 1660, 1592, 1504, 1444, 1414, 1332, 1264,1240, 1140, 1018, 874 cm⁻¹.

Step-2

Preparation of methyl[4-(3,4-dimethoxyphenyl)-4]-oxo-butyrate (4)R₁═R₂═OCH₃)

The 4-(3,4-dimethoxyphenyl)-4-oxo-butyric acid (5 g.) in diethyl etheris esterified with a freshly prepared ethereal solution of diazomethaneto furnish the corresponding ester in quantitative yield, which oncrystallization from ethyl acetate/n-hexane gave colorless needles of 4mp 87° C., analyzed for C₁₃H₁₆O₅ (found C 62.14, H 6.41 requires C61.89, H 6.39).

¹H NMR (CDCl₃): 2.76 (2H,t,J=7.0 Hz, H-2), 3.22 (2H, t, J=7.0 Hz, H-3),3.56 (3H,s, OCH₃), 3.96 (6H, s, 2x OCH₃), 6.94 (1H, d, J=8.5 Hz, Ar—H),7.68 (2H, m, Ar—H).

₁₃C NMR: 27.7, 32.2, 51.58, 55.3, 55.4, 109.7, 122.1, 129.3, 148.3,152.7, 174.2, 196.3.

IR(KBr): 2876, 1714, 1666, 1592, 1446, 1412, 1380, 1314, 1244, 1210,1178, 1148, 1088, 1020, 988, 914, 872, 794 cm⁻¹.

M+ at m/z: 252 (16), 221(7), 206 (8), 179 (5), 165 (61), 132 (49), 119(100), 91 (36), 89 (79), 74 (91).

Step-3

Synthesis of methyl[4-(3,4-dimethoxyphenyl)-4-hydroxy]butyrate (5)

To a stirring solution of 4 (3.3 g, 13 mmol) in DME(40 ml) at 0–5° C. isadded sodium borohydride (250 mg) in small installments and monitoredthe reaction by TLC. After the completion of the reaction the contentspoured in ice cold saturated brine solution (80 ml) and extracted withethyl acetate (5×30 ml). The combined organic layer washed with water,dried over anhydrous sodium sulphate and concentrated in vacuo. Theobtained semi solid mass on column chromatography on silica gel andelution with dichloromethane/ethyl acetate furnished the alcohol 5, asemi-solid (2.6 g) analyzed for C₁₃H₁₈O₅ (found C 62.31,H 7.22; requiresC 61.40, H 7.13).

¹H NMR (CDCl₃): 2.08(2H, m, CH2-), 2.53(2H, t, J=7.4 Hz, CH2COO),3.65(3H, s, OCH₃), 3.89(6H, 5, 2x OCH₃), 4.69(1H, t, J=6.6 Hz, H-4),6.82–6.89 (3H, m, Ar—H).

³C NMR: 30.4, 33.8, 51.9, 55.8, 55.9, 73.2, 108.9, 111.0, 118.0, 136.8,148.4, 149.1, 174.3.

IR (KBr): 3256, 2880, 1718, 1594, 1496, 1356, 1332, 1250, 1236, 1144,1030, 940, 858, 812, 760 cm⁻¹.

M+ at m/z 254 (6), 236(1), 234 (5), 218 (7), 216 (4), 204(5), 188(6),182(8), 174 (10), 164 (22), 162 (17), 137(22), 136 (100), 121 (17), 105(18), 90(27).

Step-4

Synthesis of methyl[4-(3,4-dimethoxyphenyl)-3-formyl-3-ene]-butyrate (6)

To a stirring solution of hydroxy ester 5 (2.3 g, 9 mmol) in dimethylformamide (9 ml) at 0–5° C. is added phosphoryl chloride (5 ml) slowlyfor 30 minutes. The contents further stirred for one hour maintainingthe temperature. The temperature is then raised to 35–40° C. andstirring continued for 36 hours till the completion of the reaction. Thecontents are then poured in cold water (200 ml) and the resultingprecipitate filtered. The aqueous layer extracted with ethyl acetate(3×20 ml). The combined solid and organic layer washed with water,dried, concentrated and chromatographed over silica gel using ethylacetate: chloroform (1:4) as eluent to give a light yellow compound 6(1.4 g, 59.5%). mp 61° C., analyzed for C₁₄H₁₆O₅ (found C 64.11, H6.09%; requires C 63.62, H 6.10).

¹H NMR (CDCl₃): 3.56 (2H, s, CH₂₋), 3.64 (3H, s, OCH₃), 3.86 (6H, 2xs,2x OCH₃), 6.88 (1H, d, J=8.5 Hz, Ar—H), 7.00 (3H, m, Ar—H), 7.05(1H, s,Ar—H), 7.37 (1H, s, ═CH), 9.56 (1H, s, CHO).

¹³CNMR: 30.7, 52.2, 55.9, 55.9, 111.2, 112.3, 124.1, 126.9, 133.2,149.1, 150.9, 152.2, 172.2, 193.2.

IR (KBr): 2832, 1752, 1590, 1512, 1456, 1424, 1352, 1266, 1240, 1152,1022, 864, 808 cm⁻¹

M+ at m/z: 264 (26), 263 (91), 248 (11), 235 (41), 232 (25), 204 (39),176 (100), 160 (92), 145 (60), 131 (25), 115 (25), 103(24), 91(28), 89(28).

Step-5

Synthesis of optically enrichedR(+)methyl-[4-(3,4-dimethoxyphenyl)-3-hydroxymethyl]-butyrate(7)(R₁═R₂═OCH₃)

A mixture of Baker's yeast (3 g, dry powder) and D-glucose (3 g) indistilled water (60 ml) was stirred an 30° C. in a fermentation flaskwith a bubbler for 10 minutes after which an ethanolic solution offormyl ester 6 (173 mg, 3 ml) is added to it. The mixture stirred at 30°C. for 50 hours with TLC monitoring and after the consumption of 6,filtered through a pad of celite (2 g) and extracted with chloroform(5×20 ml). The combined chloroform layer washed and dried (Sod.sulphate), concentrated under reduced pressure. The concentratedmaterial is purified over silica gel using chloroform: ethyl acetate(9:1). The purified product 7 (100 mg, 62.5%) a semi-solid is analyzedfor C₁₄H₂₀O₅ (found C 62.92, H 7.55%; requires C 62.67, H 7.50%).[α]D ²⁵−3.4° (c, 1.4, CHCl₃).

Step-6

Preparation of optically enriched R(+)4-(3,4dimethoxybenzyl)-γ-butyrolactone)—(1) (R₁═R₂=—OCH₃)

A suspension of 7 (60 mg) and dilute hydrochloric acid (10%, 5 ml)heated at 70° C. for 20 minutes with stirring. The product processed asdescribed for the preparation of racemic lactone above to furnishoptically enriched 1, mp 108–109° C., analysed for C₁₃H₁₆O₄ (found C66.12, H 6.87; requires C 66.08, H 6.82) [α]D ²⁵+10.5° (c, 0.24,CHCl₃);reported [α]D ²+23.8° (ee, 94%)^(3b).

EXAMPLE-2

Step-1

Preparation of 4-(4-methoxyphenyl)-4-oxo-butyric acid (3) (R₁ andR₂═OCH3 and (H)

The title compound was prepared from anisole (11 g, 102 mmol) andsuccinic anhydride (i2 g, 120 m mol) in presence of anhydrous aluminumchloride (30 g) by the same method as described for 2 above to furnish4-(4-methoxyphenyl)-4-oxo-butanoic acid in 84.6% yield, which onpurification and crystallization from methanol/ethyl acetate (1:9)produced white crystals of 3, mp142–43° C., analyzed for C₁₁,H₁₂, O₄(found C64.21, H5.86; requires C63.45, H5.80%).

¹H NMR (CDCl₃₋+DMSO-d₆): 2.70 (2H, t, J=6.5 Hz, H-2), 3.26 (2H, t, J=6.5Hz, H-3), 3.93 (3H, s, OCH₃), 7.04 (2H, d,J=8.5 Hz, Ar—H), 8.05 (2H, d,J=8.5, Ar—H).

¹³CNMR (CDCl₃+DMSO-d₆): 28.1, 32.9, 55.4, 114.2, 129.7, 130.1, 162.7,174.6, 196.7.

IR (KBr): 2844, 1670, 1600, 1574, 1426, 1358, 1316, 1246, 2120, 1026,930, 830 cm⁻¹.

M+ at m/z, 208 (40), 135 (83), 120 (12), 106 (69), 91(100), 77 (100).

Step-2

Preparation of methyl[4-(4-methoxyphenyl)-4-oxo]butyrate (4) (R₁ and112=OCH₃ and H)

The 4-oxo-4-phenyl butyric acid derivative (3) (10.16 g) was esterifiedin dry methanol (25 ml) in presence of concentrated sulfuric acid (0.5ml) and refluxing the contents on a water bath for an hour and removingthe solvent at reduced pressure after neutralization of the acidfollowed by column chromatography over silica gel to furnish 4 (10.90g), which is crystallized from ethyl acetate:hexane (1:4) mp 46° C.analyzed for C₁₂H₁₄ O₄ (found C65.46, H 6.42; requires C 64.85, H6.34%).

1H NMR (CDCl₃): 2.75 (2H, t, J=6.5 Hz, H-2), 3.28 (2H, t, J=6.5 Hz,H-3), 3.75 (2H, t, COOCH₃), 3.90 (3H, s, OCH₃), 7.00 (2H, d,J=8.5 Hz,Ar—H), 8.05 (2H, d, J=8.5, Ar—H).

¹³C NMR: 28.1, 33.0, 51.8, 55.45.5, 113.8129.6, 130.3163.6, 173.5,196.6.

IR (KBr): 2844, 1704, 1670, 1600, 1516, 1426, 1358, 1310, 1'240, 1174,1120, 1060, 1022, 986, 944, 830 cm⁻¹.

M+ at m/z, 222 (13), 191(19), 135 (100), 107 (18), 97 (27), 92(27), 77(37).

Step-3

Synthesis of methyl[4-(4-methoxyphenyl)-4-hydroxy]butyrate (5)

Reduction of (4) was carried out with sodium borohydride (7.0 g, 31mmol) by a similar process as described in example 1, the reducedproduct purified by column chromatography over silica gel usingdichloromethane: ethyl acetate (19:1) as eluant to give a semi-solid 5(6.4 g) which is analyzed for C₁₂H₁₆O₄ (found C 64.93, H 7.23; requiresC64.27, H 7.19%).

¹H NMR (CDCl₃): 1.98–2.10 (2H, m, H-3), 2.40(2H, t, J=7 Hz, H-2), 3.65(3H, s, COOCH₃), 3.83 (3H, s, OCH₃), 4.66 (1H, J=6.5 Hz, H-4), 6.94(2H,d, J=8.5 Hz, Ar—H), 7.33(2H, d, J=8.5 Hz, Ar—H).

¹³C NMR: 30.3, 33.7, 51.5, 55.07, 72.6, 113.6, 126.9, 131.0, 136.3,158.8, 174.2.IR (KBr): 3392, 2884, 1712, 1678, 1604, 1512, 1440, 1362,1240, 1172, 1114, 1060, 1026, 944, 888 cm⁻¹.

M+ at m/z: 224 (2), 223 (6), 206(3), 205 (7), 191 (15), 149 (21), 136(100), 134 (21), 108 (28), 93 (12), 76 (29).

Step-4

Synthesis of methyl[4-(4-methoxyphenyl)-3-formyl-3-ene]-butyrate (6)

Formylation of 5 (4.5 g, 20 mmol) was carried out with Vilsmeiersreagent as described in example 1. The product purified by columnchromatography with petroleum ether: ethyl acetate (9:1) to furnish 6 asa light yellow solid (2.38 g, 51%), mp 54–56° C., analyzed for C₁₃H₁₄O₄(found C 67.13, H 6.09; requires C66.65, H 6.02).

¹H NMR (CDC₁₃): 3.59 (2H, s, CH₂), 3.72(3H, s, COOCH₃), 3.89 (3H, s,OCH₃), 7.03 (2H, d, J=8.5 Hz, Ar—H), 7.53(1H, s, ═CH), 7.56 (2H, d,1=8.5 Hz, Ar—H), 9.66 (1H, s, CHO).

¹³C NMR: 30.7, 52.3, 55.5, 114.6, 126.8, 131.3, 133.3, 148.3, 161.4,171.0, 194.3.

IR (KBr): 2828, 1722, 1666, 1632, 1602, 1494, 1452, 1438, 1416, 1380,1340, 1316, 1306, 1254, 1200, 1166, 1066, 1018, 1004, 942, 912, 878,834, 772 cm⁻¹.

M+ at m/z: 234(6), 233 (42), 205 (96), 202 (31), 174 (31), 159 (24), 146(100), 134 (14), 107 (17).

Synthesis of optically enriched R(+)4-(4-methoxybenzyl)-y butyrolactone(1) (R₁ and R₂=—OCH₃ and H)

An ethanolic solution of 6 (160 mg, 3 ml) is added to a stirring mixtureof Baker's yeast (dry powder, 2.5 g) and D-glucose (2.1) in distilledwater (80 ml, pH 6.8) and the contents stirred at 30° C. under anaerobicconditions using a bubbler. The reaction is monitored by TLC and afterthe consumption of the starting material the contents worked up by themethod as described in example 1 to furnish crude bio-product (0.13 g)which on chromatographic purification on silica gel column and elutionwith pet.

ether: ethyl acetate (9:1) gave (+)−1 (80 mg, 57%) analyzed for C₁₂H₁₄O₃ (found C 70. 13, H 6.18; requires C 69.89, H 6.84).

¹H NMR (CDCl₃): 2.27 (1H, dd, J=6.7 & 17.45 Hz, H-2), 2.52–2.72(4H, m,2x CH2), 3.80 (3H, s, OCH₃), 4.04 (1H, dd, J=5.90 & 8.17 Hz, CH₂O),4.31(1H, dd, J=6.65 & 9.03 Hz, —OCH₂), 6.81(2H, d, J=8.5 Hz, Ar—H), 7.08(2H, d, J=8.5 Hz, Ar—H).

¹³C NMR: 34.3, 37.3, 38.0, 55.2, 72.7, 113.8, 130.0, 130.3, 158.5,177.0.

IR (KBr): 2884, 2848, 1732, 1614, 1510, 1460, 1378, 1356, 1302, 1248,1176, 1030, 846, 834, 752 cm⁻¹

M+ at m/z: 206 (8), 192(3), 147 (6), 121 (100), 103 (8), 91(20), 78(35).

ADVANTAGES

-   1. The synthetic process for the preparation of optically enriched    substituted β-benzyl-γ-butyrolactone is novel.-   2. The synthetic process is facile and economical-   3. The yield of the final product optically enriched substituted    β-benzyl-γ-butyrolactone is moderate to good.-   4. Use of enzymes is being made for generation of chirality at the    intermediate stage, which makes the process environmental friendly.-   5. The final product itself possess biologically active or can    easily be as a intermediates for the preparation of other class of    biologically active compounds.

1. A process for preparing optically enriched substitutedR(+)β-benzyl-γ-butyrolactones having the general formula

wherein, R₁ and R₂ independently represent the following groups R₁═R₂═H,OH, —OC_(n)H_(2n+1) (n=1 to 8), NH₂, or CF₃ R₁ and R₂ together represent—O(CH₂)_(m)O— where m=2 to 4 and said process comprises the steps of: a)reacting alkoxybenzene having the following formula

wherein R₁ and R₂ are as mentioned above, with succinic anhydride, aLewis acid in an inert solvent at a temperature in the range of 0–5° C.,b) esterifying the product 4-keto-4-phenyl-butyric acid having thefollowing formula

obtained in step (a) with an alcohol and an acid to yield4-keto-4-phenyl butyrate having the following formula

c) reducing the keto group of the compound having the formula obtainedin step (b) with a metal hydride catalyst in the presence of hydrogengas to yield the corresponding secondary alcohol 4-hydroxy-4-phenylbutyrate having the following formula

d) formylating the compound having the formula obtained in step (c) withan equimolar mixture of phosphoryl choloride and dimethyl formamide toproduce at a temperature in the range of about −5° C. to 50° C. forabout 36 hours 4-phenyl-3-formul-3ene-butrylate having the followingformula

e) catalyzing the unsaturated formyl ester having formula obtained instep (d) with a yeast selected from the group consisting of Baker'syeast, Candida spp. or Pichia spp. to obtain an optically enrichedR(−)dihydro primary alcohol having the following formula

at a temperature of about 30° C. for about 50 hours or to obtain acompound having said general formula, wherein R₂ substituent is H; andf) cyclizing the dihydro primary alcohol having the formula from step(e) with an acid at a temperature of about 70° C. for 20 minutes toproduce substituted R(+)β-benzyl-γ-butyrolactone having said generalformula.
 2. The process as claimed in claim 1, wherein in step (a) theLewis acid is selected from the group consisting of anhydrous aluminumtrichloride, aluminum tribromide, zinc chloride and boron trifluorideethereate.
 3. The process as claimed in claim 2, wherein the selectedLewis acid is anhydrous aluminum chloride.
 4. The process as claimed inclaim 1, wherein in step (a) said inert solvent is selected from thegroup consisting of nitromethane, carbon disulfide and nitrobenzene. 5.The process as claimed in claim 1, wherein in step (b) the alcohol isselected from the group consisting of methanol, ethanol, propanol ormixtures thereof.
 6. The process as claimed in claim 1, wherein in step(c) the catalyst is selected from the group consisting of palladium,platinum and nickel.
 7. The process as claimed in claim 1, wherein instep (c) the metal hydride is selected from the group consisting oflithium aluminum hydride, sodium borohydride, and sodiumcyanoborohydride.
 8. The process as claimed in claim 1, wherein in step(f) the acid is selected from the group consisting of dilute sulfuricacid, hydrochloric acid and phosphoric acid.
 9. The process as claimedin claim 4, wherein the selected inert solvent is nitrobenzene.
 10. Theprocess as claimed in claim 7, wherein the selected metal hydride issodium borohydride.
 11. The process as claimed in claim 1, wherein instep (a) said inert solvent is selected from the group consisting ofdimethyl ether, tetrahydrofuran, ethyl acetate or mixtures thereof. 12.The process as claimed in claim 8, wherein the selected acid is dilutehydrochloric acid.